This SBIR Phase I proposal is intended to demonstrate the feasibility of developing a novel and effective therapeutic agent for acute radiation injury. The threat of nuclear terrorism remains high and there is a possibility of a nuclear power plant leak, both of which can cause acute radiation injury at a large scale. Currently, there are no therapeutic agents available for the mitigation or treatment of acute radiation injury in a setting of mass exposure. Thus, there is an urgent unmet medical need for an effective mitigator to treat people exposed to acute radiation. Milk fat globule epidermal growth factor-factor VIII (MFG-E8) was identified as a potential effective radiation mitigator based on its ability to enhance apoptotic cell clearance, reduce inflammation, and maintain intestinal barrier homeostasis. Using a rat model of total body irradiation (TBI), we have discovered that administration of recombinant human MFG-E8 (rhMFG-E8) for 7 days increased the survival rate of rats exposed to 10-Gy TBI from 30% in the vehicle to 75% and 60% when treatment was initiated at 24h and 48h post-TBI, respectively. rhMFG-E8 reduced body weight loss and improved the intestinal integrity with increased villus length and reduced Goblet cell to enterocyte ratio after TBI. Moreover, rhMFG-E8 decreased gut permeability after radiation injury, leading to a reduction of bacterial translocation and endotoxemia. In addition, we have produced biologically active rhMFG-E8 with >99% purity for future commercialization. Based on these novel findings, we hypothesize that rhMFG-E8 can be developed as an effective post-exposure mitigator for acute radiation injury. In this proposal, we will determine the optimal dose of rhMFG-E8 to rescue mice exposed to TBI and the dose modification factor (DMF) of rhMFG-E8 to treat mice 24h post-TBI. We will also evaluate the effect of rhMFG-E8 on hematopoietic and gastrointestinal damages in mice exposed to TBI. Our ultimate goal is to obtain the FDA approval to use rhMFG-E8 as a safe and effective treatment for victims suffering from acute radiation injury in a large scale exposure setting.